Field of Invention
This invention relates to a novel chimeric virus and immunogenic compositions containing the chimeric virus which, when administered to an animal, can induced an immune response to both NDV and ILTV. This invention relates more specifically to NDV LaSota strain expressing ILTV gB or gD antigens, immunogenic compositions containing one or both chimeric viruses, and methods of use thereof.
The Sequence Listing submitted in text format (.txt) filed on Feb. 13, 2015, named “Sequence_Listing.txt”, (created on Feb. 25, 2014, 161 KB), is incorporated herein by reference.
Description of the Prior Art
Infectious laryngotracheitis (ILT), classified as a disease requiring notification to the World Organization for Animal Health (OIE), is a highly contagious acute respiratory disease that has become a major problem in the U.S. poultry industry in recent years and is caused by infectious laryngotracheitis virus (ILTV), formally called Gallid herpesvirus type 1 (GaHV-1). For protection, chickens are vaccinated multiple times with live strains that were attenuated by either multiple passages in embryonated eggs (chicken embryo origin [CEO] or in tissue culture (tissue culture origin) [TCO]). Although these vaccines protect against clinical disease, they have residual virulence which is exacerbated by continued infections of naive birds from productively infected animals and latent carriers. Moreover, the CEO vaccine strain has been demonstrated to mutate and become more virulence simply by bird-to-bird passage. Because of this characteristic, it is believed that U.S. vaccine strains have mutated to become more virulent and these “revertants” have become the dominant field strains in the poultry population. As a result of this increased virulence in the circulating virus and the use of high-density poultry housing, there is a continuous reservoir of viruses (both virulent and vaccinal) in flocks that is capable of evolving to higher levels of virulence.
To overcome problems associated with live attenuated ILTV vaccine strains, inactivate whole-virus vaccines and turkey herpesvirus (HVT)- and fowl poxvirus (FPV)-vectored constructs containing ILTV antigens have been developed and tested in protection studies. Although these vaccines are completely safe when administered at different ages, they induce only partial protection when compared with that induced by a live-attenuated ILTV vaccine. As such, a significant need exists for a new ILT vaccine strategy, particularly regarding the development of next generation vaccines or immunogenic compositions that are inexpensive, incapable of virulent reversion, and unable to transfer horizontally to naïve birds, in order to control the disease and prevent devastating losses.
ILTV, an alphaherpesvirus, possesses at least ten envelope glycoprotein genes, including glycoprotein B (gB) and glycoprotein D (gD) which are the most highly conserved herpesvirus structural glycoproteins. Glycoprotein B is essential for infectivity and is involved in membrane fusion and virus penetration. Glycoprotein D is essential for most herpesviruses and functions as a receptor for virus binding to susceptible cells. In addition, gB elicits high titers of neutralizing antibodies and cell-mediated immune responses, and has been shown to be a strong candidate antigen for recombinant subunit vaccines.
Newcastle disease (ND), caused by infection of virulent Newcastle disease virus (NDV), is one of the most serious infectious diseases in poultry. It has been classified into one serotype and three different pathotypes: velogenic (highly virulent), mesogenic (moderately virulent), and lentogenic (low virulence) viruses. Velogenic strains can cause severe disease, characterized by extensive lesions and high mortality in both the laboratory and field, and such outbreaks require reporting to the World Organization for Animal Health (OIE) by member nations.
Vaccination combined with strict biosecurity practices have been recommended for controlling NDV outbreaks for over 60 years. The NDV LaSota strain, a naturally-occurring low virulence NDV strain, has been routinely used as a live vaccine throughout the world for more than fifty years to prevent ND. This vaccine strain induces strong immunity both locally and systemically and can be readily administered through drinking water supplies or by directly spraying the birds. The LaSota vaccine has been proven to be safe and stable, and there are no reports of virulence reversion or recombination for this vaccine strain to generate new virulent strains.
NDV is a negative-sense single-strand RNA virus which contains a negative-sense RNA inside its capsid. After entry into a cell, the virus/cell makes positive-sense RNAs (mRNA and anti-genomic RNA) which are used to generate viral proteins and nascent negative-sense single-strand RNAs which are packaged into virions. The negative-sense ssRNA sequence of NDV is the reverse complement of the cDNA sequence of the viral RNA.
Others have explored using recombinant Newcastle disease virus (rNDV) LaSota strain (rLS) as a vector for presenting heterologous antigens to an animal's immune system. Much of this work involved the use of rNDV vector for combating human diseases, although some involved vaccines for avain pathogenic microorganisms. See, Bukreyev and Collins, Curr. Opin. Mol. Ther. 10(1):46-55 (2008) using of rNDV as a vector for respiratory tract disease antigens for humans; Bukreyev, et al., J. Virology 79(21):13275-84 (2005) examining use of rNDV expressing human parainfluenza virus type 3 hemagglutinin-neuraminidase protein; DiNapoli, et al., Proc. Natl. Acad. Sci., 104(23):9788-93 (2007) examining rNDV as vector for severe acute respiratory syndrome-associated coronavirus spike S glycoprotein; DiNapoli, et al., Vaccine 27(10):1530-9 (2009) examining efficacy of various routes of administration of rNDV-vectored vaccines; Ge, et al., J. Virol. 81:150-158 (2007) examining rNDV expressed an H5 subtype avian influenza virus hemagglutinin; Ge, et al., Avian Dis. 54:294-296 (2010) examining rNDV expressed an H9 subtype avian influenza virus hemagglutinin; Huang, et al., Poultry Science 82:899-906 (2003) reviews rNDV as vaccine vector for veterinary use; Nakaya, et al., Virol. 75:11868-11873 (2001) examining rNDV expressing influenza virus hemagglutinin; Nayak, et al., PloS One 4(8) e6509 (2009) examining rNDV expressing H5 influenza hemagglutinin; Park, et al., Proc. Natl. Acad. Sci. 103:8203-8208 (2006) examining rNDV expressing ectodomain of an H7 avian influenza virus hemagglutinin; and Swayne, et al., Avian Dis. 47:1047-1050 (2003) examining expression of avian influenza virus H7 hemagglutinin in rNDV.
Previously, a chimeric virus of NDV LaSota strain and a heterologous antigen (glycoprotein from three separate strains of avian metapneumovirus (aMPV)) was generated and evaluated as an immunogenic composition to generate a protective immune response against both NDV and aMPV (aMPV-A, aMPV-B, or aMPV-C) (Hu, et al., Vaccine 29:8624-8633 (2011) and Yu, et al., World J. of Vaccines 3:130-139 (2013)). The DNA sequence of the heterologous antigen was placed between the F gene and HN gene of the NDV LaSota strain. In these three cases, the chimeric virus failed to induce a sufficiently robust immune response in the inoculated animal to protect the inoculated animal against the disease caused by aMPV (turkey rhinotracheitis), even when the animal was exposed to the aMPV strain from which the glycoprotein (heterologous antigen) was obtained. While not wishing to be bound to any hypothesis, the incomplete protection could have resulted from one or more factors including, but not limited to, the use of a weak antigen which was unable to stimulate a sufficiently robust immune response to protect the inoculated animal, low production of the foreign antigen by the cell because of the location the sequences encoding the heterologous antigen were inserted into NDV's genomic RNA, and poor replication of the chimeric virus in the inoculated animal.
To overcome numerous problems associated with live attenuated ILTV strains, a recombinant NDV LaSota strain is used as a live vaccine vector to express ILTV's gB or gD genes (a chimeric virus). This chimeric vaccine is an immunogenic composition that, after administration to an animal, induces an immune response in the recipient to both NDV and ILTV and prevents both diseases. In light of prior failures of a chimeric virus of NDV LaSota strain and a heterologous antigen, it is surprising and unexpected result that the animals inoculated with the chimeric virus of the present invention generate a sufficiently robust immune response to be protected from ILTV and the disease it causes.